Myocardial Dysfunction: A Primary Cause of Death Due To Severe Malaria in A Plasmodium falciparum-Infected Humanized Mouse Model.

  • Odaro Stanley Imade Mail Department of Biological Sciences, College of Natural & Applied Sciences, Igbinedion University, Okada, Edo State, Nigeria.
  • Faith Iguodala Akinnibosun Microbiology Department, Faculty of Life Sciences, University of Benin, Benin City, Edo State, Nigeria.
  • Bankole Henry Oladeinde Department of Medical Microbiology, College of Health Sciences, Igbinedion University, Okada, Edo State, Nigeria.
  • Osaro Iyekowa Chemistry Department, Faculty of Chemical Sciences, University of Benin, Benin City, Nigeria.
Humanized, Immunosuppressed, Myocardial, Parasitemia, Therapy


Background: Our study aimed at substantiating the recent claim of myo-cardial complications in severe malaria by experimentally inducing severe Plasmodium falciparum infection in a humanized mouse model employed as human surrogate.Methods: Twenty five humanized mice were inoculated with standard in vitro cultured P. falciparum and blood extracts collected from the inner cardiac muscles of infected mice that died were examined for the presence of the infectious cause of death. The therapeutic effect of quinine on 7 mice se-verely infected with P. falciparum was also evaluated.Results: All the 25 humanized mice inoculated with the in vitro cultured P. falciparum revealed peripheral parasitemia with a total of 10 deaths recorded. Postmortem examination of the inner cardiac muscles of the dead mice also revealed massive sequestration of mature P. falciparum as well as significant infiltration of inflammatory cells such as lymphocytes and monocytes. Post-mortem evaluation of the inner cardiac muscles of the P. falciparum-infected mice after quinine therapy showed significant decline in parasite density with no death of mice recorded.Conclusions: Data obtained from our study significantly corroborated the findings of myocardial dysfunction as the primary cause of death in recent case reports of humans infected with P. falciparum.


World Health Organization (WHO). Severe falci-parum malaria. Trans Royal Soc Trop Med Hyg. 2000; 94: 1 – 90.

Marsh K, Forster D, Waruiru C, Nwangi I, Win-stanley M, Marsh V. Indicators of threatening malaria in African children. N Eng J Med. 1995; 332: 1399 – 1404.

Dondorp AM, Lee SJ, Faiz MA, Mishra S, Price R, Tjitra E. The relationship between age and the manifestations of and mortality associated with severe malaria. Clin Infect Dis. 2008; 47: 151 – 157.

Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI. The global distribution of clinical epi-sodes of Plasmodium falciparum malaria. Na-ture. 2005; 434: 214 – 217.

Clark IA, Awburn MM, Harper CG, Liomba NG, Molyneux ME. Induction of HO-1 in tissue macrophages and monocytes in fatal falciparum malaria and sepsis. Malar J. 2003; 2: 41. 6. Wassmer SC, Medana IM, Turner GDH, Mai NTH, Day NPJ, Hien TT. Fatal cerebral malaria: distinct microvascular pathologies in children and adult patients. Int J Parasitol. 2008; 38: S44.

Gunther A, Grobusch MP, Slevogt H, Abel W, Burchard GD: Myocardial damage in falciparum malaria detectable by cardiac troponin T is rare. Trop Med Int Health. 2004; 8: 30 – 32.

Rowe JA, Claessens A, Corrigan RA, Arman M. Adhesion of Plasmodium falciparum-infected eryth-rocytes to human cells: molecular mechanisms and therapeutic implications. Expert Rev Mol Med. 2009; 11: e16.

Planche T., Krishna S. Severe malaria: metabolic complications. Curr Mol Med. 2006; 6: 141–153. 10. van der Heyde HC, Nolan J, Combes V, Gramaglia I, Grau GE. A unified hypothesis for the genesis of cerebral malaria: sequestration, in-flammation and hemostasis leading to mi-crocirculatory dysfunction. Trends Parasitol. 2006; 22: 503 – 508.

Schofield L. Intravascular infiltrates and organ-specific inflammation in malaria pathogenesis. Immunol Cell Biol. 2007; 85: 130 – 137.

Engwerda CR, Beattie L, Amante FH. The im-portance of the spleen in malaria. Trends Para-sitol. 2005; 21: 75 – 80.

Schofield L, Grau GE. Immunological processes in malaria pathogenesis. Nat Rev Immunol. 2005; 5: 722 – 735.

Amante FH, Haque A, Stanley AC, Rivera Fde L, Randall LM, Wilson YA. Immune-mediated mechanism of parasite tissue sequestration dur-ing experimental cerebral malaria. J Immunol. 2010; 185: 3632 – 3642.

Renia, L, Potter SM, Mauduit M, Rosa DS, Kayi-banda M, Deschemin JC. Pathogenic T cells in cerebral malaria. Int J Parasitol. 2006; 36: 547 – 554.

Boeuf PS, Loizon S, Awandare GA, Tetteh JK, Addae MM, Adejei GO. Insights into dereg-ulated TNF and IL-10 production in malaria: Implications for understanding severe malaria anaemia. Mal J. 2012; 11:253.

Brown H., Turner G., Rogerson S., Tembo M, Mwenechanya J, Molyneux M. Cytokine expres-sion in the brain in human cerebral malaria. J In-fect Dis. 1999; 180: 1742 – 1746.

Taylor-Robinson AW. Validity of modeling cer-ebral malaria in mice: Argument and counter ar-gument. J Neuroparasitol. 2010; 1: 5. 19. Medana IM, Day NP, Hien TT, Mai NT, Bethell D, Phu NH. Axonal injury in cerebral malar-ia. Am J Pathol. 2002; 160: 655 – 666. 20. Medana IM, Turner GD, Human cerebral malar-ia and the blood-brain barrier. Int J Parasi-tol. 2006; 36: 555 – 568. 21. Dorovini-Zis K, Schmidt K, Huynh H, Fu W, Whitten R, Milner D. The neuropathology of fatal cerebral malaria in Malawian children. Am J Pathol. 2011; 178: 2146 – 2158.

Nieman A, de Mast Q, Roestenberg M, Wie-rsma J, Pop G, Stalenhoef A. Cardiac complica-tion after experimental human malaria infection: a case report. Mal J. 2009; 8: 277.

Costenaro P, Benedetti P, Facchin C, Mengoli C, Pellizzer C. Fatal myocarditis in course of Plas-modium falciparum: Case report and review of car-diac complications in malaria. Case Rep Med. 2011; 2011: 202083.

Javeed A,Hou Y,Duan K,Zhang B,Shen H,Cao Y, Zhao Y. Aspirin significantly decreases the nonopsonic phagocytosis and immunogenicity of macrophages in mice. Infl Res. 2011; 60: 389 – 398.

Bellahsene A, Forsgren A. Effect of doxycycline on immune response in mice. Infect Immun. 1985; 48: 556 – 559.

Imade OS, Iyekowa O, Edema MO, Akinni-bosun FI, Oladeinde BH, Olley M. A cost-effec-tive scheme developed for studying human ma-laria caused by Plasmodium falciparum. J Nat Sci Res. 2012; 2 (6): 1 – 9.

Moreno A, Badell E, Rooijen NV, Druilhe P. Human malaria in immunocompromised mice: New in vivo model for chemotherapy studies. Antimicrob Agent Chemother. 2001; 45: 1847 – 1853.

Trager W, Jensen JB. Human malaria parasites in continuous culture. 1976. J Parasitol. 2005; 91: 484 – 486.

Lambros C, Vanderberd J. Synchronization of P. falciparium erythrocyte stages in culture. J Parasitol. 1979; 65: 418 – 420.

Schlam O, Caroll E. Veterinary Hematology. 3rd ed. USA: Lea and Tebiger; 1975. PP. 207 – 209.

World Health Organization (WHO). Basic Ma-laria Microscopy Part 1. Learner’s Guide, 2nd ed. Switzerland: World Health Organization; 2009. PP. 21 – 68.

Moody, A. (2002). Rapid Diagnostic Tests for Malaria Parasites. Clin Microbial Rev. 15, 66 – 78.

Bassey AS, Okokon JE, Etim EI, Umoh FU, Bassey E. Evaluation of the in vivo antimalarial activity of ethanolic leaf and stem bark extracts of Anthocleista djalonenis. Indian J Pharmacol. 2009; 41: 258 – 261.

Day NP, Hien TT, Schollaardt T, Loc PP, Chuong LV, Chau TT. The prognostic and pathophysiologic role of pro- and anti-inflammatory cytokines in severe malaria. J In-fect Dis. 1999; 180: 1288 – 1297.

Naik RS, Branch OH, Woods AS et al. Phospha-tidylinositol anchors of Plasmodium falciparum: Mo-lecular characterization and naturally elicited anti-body response that may provide immunity to malaria pathogenesis. J Exp Med. 2000; 192: 1563 –1576.

Clark IA, Budd AC, Alleva LM, Cowden WB. Human malarial disease: a consequence of in-flammatory cytokine release. Mal J. 2006; 5: 85. 37. World Health Organization (WHO). Guide-lines for the treatment of malaria. 2nd ed. Switzerland: World Health Organization; 2010. pp. 194.

Arnold l, Tyagi RK, Maija P, Swetman C, Gleeson J, Perignon J. Further improvements of the P. falciparum humanized mouse model. PLoS One 2011; 6: e18045.

Santini SM, Rizza P, Logozzi MA, Sestili P, Gherardi G, Lande R. The SCID mouse reaction to human peripheral blood mononuclear leu-kocyte engraftment: Neutrophil recruitment in-duced expression of a wide spectrum of murine cytokines and mouse leukopoiesis, including thymic differentiation. Transplantation 1995; 60: 1306 – 1314. 40. Kirkiles-Smith NC, Harding MJ, Shepherd BR, Fader SA, Yi T, Wang Y. Development of a humanized mouse model to study the role of macrophages in allograft injury. Transplantation 2009; 87: 189 – 197.

Arnold L, Tyagi RK, Mejia P, Rooijen NV, Perignon J, Druilhe P. Analysis of innate defenses against Plasmodium falciparum in immunodeficient mice. Mal J. 2010; 9: 197 – 208.

Van-Rooijen N. The liposome-mediated macro-phage ‘suicide’ technique. J Immunol Methods. 1989; 124: 1 – 6.

Badell E, Oeuvray C, Moreno A, Soe S, Rooijen N, Bouzidi A. Human malaria in immuno-compromised mice: An in vivo model to study defense mechanisms against Plasmodium falciparum. J Exp Med. 2000; 192: 1653 – 1660.

Ishikawa F, Yasukawa M, Lynos B, Yoshida S, Mujamoto T, Yoshimoto G. Development of functional human blood and immune systems in NOD/SCID/IL2 receptor γ chainnull mice. Blood 2005; 106: 1565 – 1573.

Pukrittayakamee S, Clemens R, Pramoolsinsap C, Karges HE, Vanijanonta S, Bunnag D. Poly-morphonuclear leucocyte elastase in Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg. 1992; 86: 598 – 601.

Silamut K, White NJ. Relation of the stage of parasite development in the peripheral blood to prognosis in severe falciparum malaria. Trans R Soc Trop Med Hyg. 1993; 87: 436 – 443.

Ho M, White NJ. Molecular mechanisms of cy-toadherence in malaria. Am J Physiol Cell Phys-iol. 1999; 276: C1231 – 1242.

Horata N, Kalambaheti T, Craig A, Khusmith S. Sequence variation of PfEMP1-DBLα in asso-ciation with rosette formation in Plasmodium falci-parum isolates causing severe and uncomplicated malaria. Mal J. 2009; 8: 184.

Fibach E, Rachilewitz E. The role of oxidative stress in hemolytic anemia. Curr Mol Med. 2008; 8: 609 – 619.

Meslin B, Barnadas C, Boni V, Latour C, Mon-brison F, Kaiser K. Features of apoptosis in P. fal-ciparum erythrocytic stage through a putative role of pfMCA1metacaspase-like proteins. J Infect Dis. 2007; 195: 1852 – 1859.

Kumar S, Guha M, Choubey V, Maity P, Sri-vastava K, Puri SK. Bilirubin inhibits Plasmodium falciparum growth through generation of reactive oxygen species. Free Radic Biol Med. 2008; 44: 602 – 613.

McMorran BJ, Marshall VM, deGraaf C, Drys-dale KE, Shabbar M, Smyth GK. Platelets kill in-traerythrocytic malarial parasites and mediate sur-vival to infection. Science 2009; 323: 797 – 800.

How to Cite
Stanley Imade O, Iguodala Akinnibosun F, Henry Oladeinde B, Iyekowa O. Myocardial Dysfunction: A Primary Cause of Death Due To Severe Malaria in A Plasmodium falciparum-Infected Humanized Mouse Model. Iran J Parasitol. 8(4):499-509.